Esterhuizen scored 119 as South Africa were put into bat and compiled 335-9 in their 50 overs before dismissing their hosts for 178 at the Namibia Cricket Ground in Windhoek.
Esterhuizen and Tony de Zorzi, who made 79 runs, put on 183 runs for the second wicket to lay the foundation for their team's success while Namibia quick Jack Brassell took 4-64.
In reply, Namibia's opening three batsmen were dismissed without scoring and they were teetering at 32-5 in the 11th over before captain Gerhard Erasmus offered some resistance, scoring 68. But they were dismissed with 8.1 overs remaining, well short of the target.
South Africa's opening bowlers Duan Jansen (4-31) and Ethan Bosch (3-27) did the early damage.
The visitors also had a comfortable victory in their first meeting on Wednesday, winning by 99 runs on the Duckworth-Lewis-Stern method in a rain-affected clash.
The two countries, who are co-hosting next year's World Cup along with Zimbabwe, will on Sunday complete the last game of their first-ever ODI series against each other.